Pleiotropic genes in psychiatry: Calcium channels and the stress-related FKBP5 gene in antidepressant resistance

Chiara Fabbri, Filippo Corponi, Diego Albani, Ilaria Raimondi, Gianluigi Forloni, Koen Schruers, Siegfried Kasper, Alexander Kautzky, Joseph Zohar, Daniel Souery, Stuart Montgomery, Carlotta Pia Cristalli, Vilma Mantovani, Julien Mendlewicz, Alessandro Serretti

Research output: Contribution to journalArticle

Abstract

A candidate gene and a genome-wide approach were combined to study the pharmacogenetics of antidepressant response and resistance. Investigated genes were selected on the basis of pleiotropic effect across psychiatric phenotypes in previous genome-wide association studies and involvement in antidepressant response. Three samples with major depressive disorder (total=671) were genotyped for 44 SNPs in 8 candidate genes (CACNA1C, CACNB2, ANK3, GRM7, TCF4, ITIH3, SYNE1, FKBP5). Phenotypes were response/remission after 4weeks of treatment and treatment-resistant depression (TRD). Genome-wide data from STAR*D were used to replicate findings for response/remission (n=1409) and TRD (n=620). Pathways including the most promising candidate genes were investigated in STAR*D for involvement in TRD. FKBP5 polymorphisms showed replicated but nominal associations with response, remission or TRD. CACNA1C rs1006737 and rs10848635 were the only polymorphisms that survived multiple-testing correction. In STAR*D the best pathway associated with TRD included CACNA1C (GO:0006942, permutated p=0.15). Machine learning models showed that independent SNPs in this pathway predicted TRD with a mean sensitivity of 0.83 and specificity of 0.56 after 10-fold cross validation repeated 100 times. FKBP5 polymorphisms appear good candidates for inclusion in antidepressant pharmacogenetic tests. Pathways including the CACNA1C gene may be involved in TRD and they may provide the base for developing multi-marker predictors of TRD.

Original languageEnglish
Pages (from-to)203-210
Number of pages8
JournalProgress in Neuro-Psychopharmacology and Biological Psychiatry
Volume81
DOIs
Publication statusPublished - Feb 2 2018

Keywords

  • Adult
  • Calcium Channels/genetics
  • Depressive Disorder, Major/drug therapy
  • Depressive Disorder, Treatment-Resistant/drug therapy
  • Female
  • Genetic Association Studies
  • Genetic Pleiotropy
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Middle Aged
  • Pharmacogenomic Variants
  • Polymorphism, Single Nucleotide
  • Tacrolimus Binding Proteins/genetics
  • Treatment Outcome

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  • Cite this

    Fabbri, C., Corponi, F., Albani, D., Raimondi, I., Forloni, G., Schruers, K., Kasper, S., Kautzky, A., Zohar, J., Souery, D., Montgomery, S., Cristalli, C. P., Mantovani, V., Mendlewicz, J., & Serretti, A. (2018). Pleiotropic genes in psychiatry: Calcium channels and the stress-related FKBP5 gene in antidepressant resistance. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 81, 203-210. https://doi.org/10.1016/j.pnpbp.2017.10.005